Project Summary There is an urgent need for the development of new approaches to treat patients suffering from traumatic injury, which is the most common cause of death for individuals below age 45 and a leading cause of death in all age groups in the US. Especially important is the search for therapeutics to address the inflammatory, metabolic and cellular injury mechanisms that result from a traumatic injury and the ensuing ischemia/reperfusion injury (IRI). Extensive preliminary results and literature reports in models of traumatic injury clearly demonstrate that carbon monoxide (CO) is cytoprotective and can limit tissue injury and organ dysfunction and reduce mortality. The pharmacology of CO administration is understood well enough that the examination of CO?s therapeutic potential for various applications is very much warranted and needed. To date, CO gas has been the modality of choice in the majority of animal studies. However, inhaled CO is not expected to be a pharmaceutically acceptable and viable option for the majority of potential clinical applications. The objective of the proposed project is to investigate a novel modality by which to administer CO as a therapeutic agent for the treatment of trauma patients using rectal and oral formulations of CO (HBI-002). The safety and tolerability of inhaled CO has been demonstrated in successful Phase 1 clinical studies supported by well-defined preclinical data sets that led to approval by the FDA for human testing. The administration of a defined dose of CO delivered by rectal or oral administration of HBI-002 obviates the problems associated with inhaled or carrier-metal bound CO releasing molecules, including environmental safety and dosing (inhaled CO) and carrier-molecule toxicity and CO release characteristics (carrier-metal bound CO). HBI-002 comprises rectal and oral formulations containing precise amounts of CO that are easily absorbed from the gastrointestinal tract. Preliminary preclinical in vivo pharmacokinetic and pharmacodynamic studies demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that HBI-002 is effective in limiting inflammation and improving outcomes in animal models as has been shown with CO gas and other forms of CO delivery and to better understand the potential mechanism(s) of the protection. Based upon these accepted paradigms, our central hypothesis that will be tested in this project is: HBI-002 prevents inflammation and end organ failure after hemorrhagic shock and trauma.